22 research outputs found
Deep-sequencing of viral genomes from a large and diverse cohort of treatment-naive HIV-infected persons shows associations between intrahost genetic diversity and viral load.
BACKGROUND
Infection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure the HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment.
METHODS
We analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure.
RESULTS
We confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-value<2.0x10-5) and Shannon entropy at AA positions which in our association analysis explained 13% of the variance in VL. Finally, equivalent analysis based on variation in HIV consensus sequences explained only 2% of VL variance.
CONCLUSIONS
Our results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes.
TRIAL REGISTRATION
Samples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site
Deep-sequencing of viral genomes from a large and diverse cohort of treatment-naive HIV-infected persons shows associations between intrahost genetic diversity and viral load.
BackgroundInfection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure of HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment.MethodsWe analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure.ResultsWe confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-valueConclusionsOur results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes.Trial registrationSamples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site
Summary of the total considered positions, explained variance and Pearson’s correlation coefficient based on the infection duration in the robustness analysis of the results when changing the sequencing depth requirement for positions to be included from 500-fold to 300-fold and 1,000-fold, respectively.
(DOCX)</p
The density plots of the mean Shannon entropy in different races of the 36 most variable positions.
(DOCX)</p
Manhattan plot of the associations between viral load (VL) and Shannon entropy at AA positions projected on the HIV genome.
Red horizontal line marks the Bonferroni p-value threshold (p = 2.0×10−5). The x-axis denotes gene AA positions. A total of 2,447 HIV AA positions are shown on the x-axis. Gag positions 1–239, Pol positions 981–1004, Rev positions 1–6 and Tat positions 1–51 are not shown, as they were not covered by the amplicons.</p
HIV genomic positions for which ≤800 samples had a minimum of 500-fold genome sequencing depth at position.
(DOCX)</p
Sixteen HIV amino acid (AA) positions where Shannon entropy was significantly associated with viral load (VL).
Sixteen HIV amino acid (AA) positions where Shannon entropy was significantly associated with viral load (VL).</p
Characteristics of 2,650 participants from the START trial included in this analysis.
IQR (interquartile range). (DOCX)</p
Joint multiple linear regression model with the Shannon entropy values from significantly associated AA positions.
P-values below the 0.05 threshold are marked in bold. (DOCX)</p
The relationship between sample’s mean Shannon entropy, viral load (VL) and infection duration.
The relationship between sample’s mean Shannon entropy, viral load (VL) and infection duration.</p